Fecal glycoprotein 2 is a marker of gut microbiota dysbiosis and systemic inflammation

Abstract

Background: Antimicrobial autoantigenic glycoprotein 2 (GP2) is an important component of the innate immune system which originates from the exocrine pancreas as well as from the small intestines. The relationship of GP2 with the intestinal microbiome as well as the systemic implications of increased fecal GP2 levels are, however, still unclear. Therefore, fecal samples from 2,812 individuals of the Study of Health in Pomerania (SHIP) were collected to determine GP2 levels (enzyme-linked immunosorbent assay) and gut microbiota profiles (16 S rRNA gene sequencing). These data were correlated and associated with highly standardised and comprehensive phenotypic data of the study participants.

Results: Fecal GP2 levels were increased in individuals with higher body mass index and smokers, whereas lower levels were found in case of preserved exocrine pancreatic function, female sex or a healthier diet. Moreover, higher GP2 levels were associated with increased serum levels of high-sensitivity C-reactive protein, loss of gut microbial diversity and an increase of potentially detrimental bacteria (Streptococcus, Haemophilus, Clostridium XIVa, or Collinsella). At the same time, predicted microbial pathways for the biosynthesis of beneficial short-chain fatty acids or lactic acid were depleted in individuals with high fecal GP2. Of note, GP2 exhibited a stronger association to overall microbiome variation than calprotectin.

Conclusion: Fecal GP2 is a biomarker of gut microbiota dysbiosis and associated with increased systemic inflammation. The intestines may be more important as origin for GP2 than pancreatic acinar cells. Future studies need to investigate the potential clinical value in disease specific patient cohorts.

Keywords: Biomarker; Exocrine; GP2; IBD; Pancreas; Pancreatitis.

Fig. 1

Contribution of GP2 levels and other important host factors to gut microbiota diversity. Shown are the two major PCo1 and PCo2 with each dot representing one individual gut microbiome sample, coloured according to the quantities of fecal GP2. The length of the blue arrows indicates the effect size of specific variable contributions to gut microbiota beta diversity. Variation in fecal GP2 and pancreatic elastase levels have the highest impact on microbial variation. BMI: Body mass index. FFS: Food frequency score (healthy diet)

Fig. 2

Association of GP2 levels with gut microbiota. Shown is a cladogram depicting microbial genera or families (continuous data) and their association with fecal GP2 levels. Significant results (q < 0.05) are depicted by a red (positive association) or blue dot (inverse association). The dot diameter corresponds to the magnitude of the regression effect estimate. Different phyla are colour coded. The analyses revealed marked gut microbiota changes in association to variation in fecal GP2 levels. G: Genus. F: (unclassified) Family

Fig. 3

Association of GP2 levels with gut microbial presence-absence patterns. Shown is a cladogram depicting microbial genera or families (presence-absence data) and their association with fecal glycoprotein 2 (GP2) levels. Significant results (q < 0.05) are depicted by a red (positive association) or blue dot (inverse association). The dot diameter corresponds to the magnitude of the regression effect estimate. Different phyla are colour coded. The analyses revealed a loss of distinct microbial taxa in individuals with higher fecal GP2 levels. G: Genus. F: (unclassified) Family

Fig. 4

Association of GP2 levels with microbial alpha diversity reduction. The barplot shows inverse associations between fecal GP2 levels and the microbial diversity scores Simpson diversity number (N2), Shannon diversity index (H), Chao1 estimator and species richness (N0). *: indicates significant results (p < 0.05)

Fig. 5

Association of GP2 levels with reduced SCFA and lactic acid biosynthesis capability. The barplot shows inverse (blue) or positive (red) associations between fecal GP2 levels and predicted microbial pathways for SCFA or lactic acid biosynthesis. Pathways that produce SCFA as primary or byproduct are coloured in blue. The analysis revealed a distinct reduction in the microbial capacity for SCFA or lactic acid biosynthesis in individuals with higher fecal GP2 levels. *: indicates significant results (q < 0.05)